The field of the invention is treating post-seizure patients to interfere with epileptogenesis.
The highest incidence of seizures during lifetime is found in the neonatal period and neonatal seizures lead to a propensity for epilepsy and long-term cognitive deficits. Here we identify potential mechanisms that elucidate a critical role for AMPARs in epileptogenesis during this critical period in the developing brain. Using a rodent model of neonatal seizures, we have previously shown that administration of antagonists of the alpha-amino-3-hydroxy-5-methyl-4-isoxazole propionic acid subtype of glutamate receptors (AMPAR) during the 48 hours following seizures prevents long-term increases in seizure susceptibility and seizure-induced neuronal injury. Hypoxia-induced seizures in postnatal day (P) 10 rats induce rapid and reversible alterations in AMPAR signaling resembling changes previously implicated in models of synaptic potentiation in vitro. Hippocampal slices removed following hypoxic seizure exhibited potentiation of AMPAR-mediated synaptic currents, including an increase in the amplitude and frequency of spontaneous and miniature excitatory post-synaptic currents (EPSCs) as well as increased synaptic potency. This increased excitability was temporally associated with rapid increase in GluR1 S845/S831 and GluR25880 phosphorylation and increased activity of the protein kinases (including CamK II, PKA and PKC) that mediate the phosphorylation of the AMPARs. Post-seizure administration of AMPAR antagonists in vivo (including NBQX, topiramate, and GYKI-53773) attenuated the AMPAR potentiation, phosphorylation and kinase activation and prevented the concurrent increase in seizure susceptibility seen in vivo. Thus, potentiation of AMPAR-containing synapses is a reversible, early step in epileptogenesis that provides a novel therapeutic targets in the highly seizure-prone developing brain.
Aspects of this disclosure were published by the inventors in Rakhade et al., J Neurosci. 2008 Aug. 6; 28(32):7979-90.